Zimmer Biomet (Switzerland)

Distributions of pairwise differences often called "mismatch distributions" have been extensively used to estimate the demographic parameters of past population expansions. However, these estimations relied on the assumption that all mutations occurring in the ancestry of a pair of genes lead to observable differences (the infinite-sites model). This mutation model may not be very realistic, especially in the case of the control region of mitochondrial DNA, where this methodology has been mostly applied. In this article, we show how to infer past demographic parameters by explicitly taking into account a finite-sites model with heterogeneity of mutation rates. We also propose an alternative way to derive confidence intervals around the estimated parameters, based on a bootstrap approach. By checking the validity of these confidence intervals by simulations, we find that only those associated with the timing of the expansion are approximately correctly estimated, while those around the population sizes are overly large. We also propose a test of the validity of the estimated demographic expansion scenario, whose proper behavior is verified by simulation. We illustrate our method with human mitochondrial DNA, where estimates of expansion times are found to be 10-20% larger when taking into account heterogeneity of mutation rates than under the infinite-sites model.

BACKGROUND: Some patients who have a total hip replacement with a second-generation metal-on-metal articulation have persistent or early recurrence of preoperative symptoms. Characteristic histological changes in the periprosthetic tissues suggested the development of an immunological response. Therefore, in order to determine the relevance of these symptoms, we performed a study of the clinical data and periprosthetic tissues associated with endoprostheses with a metal-on metal articulation that had been retrieved at revision. METHODS: Periprosthetic tissues as well as the clinical data on the patients were obtained from the first nineteen consecutive revisions performed at the treating hospitals. At the time of the revision, fourteen patients had the metal-on-metal articulation exchanged for either an alumina-ceramic or a metal-on-polyethylene articulation. Five patients received another second-generation metal-on-metal total joint replacement. Five-micrometer sections were prepared from the tissue samples, were stained with routine and immunohistochemical methods, and were examined histologically. Histological specimens from three groups of patients, two of which were treated with non-metal-on-metal implants, served as controls. RESULTS: The majority of patients had persistence of their preoperative pain or early recurrence of the pain after the original total hip replacement, and often a pronounced hip joint effusion had developed after the original replacement. Radiographic follow-up showed the development of radiolucent lines in five hips and of osteolysis in another seven hips. At the revision surgery, both the cup and the stem were found to be well fixed in nine patients. The characteristic histological features were diffuse and perivascular infiltrates of T and B lymphocytes and plasma cells, high endothelial venules, massive fibrin exudation, accumulation of macrophages with droplike inclusions, and infiltrates of eosinophilic granulocytes and necrosis. Only a few metal particles were detected. Immunohistochemical analysis demonstrated that the cellular reaction was still active. The patients who received another second-generation metal-on-metal articulation at the time of the revision had no decrease in symptoms. In the control group of tissues obtained at revisions of endoprostheses without cobalt, chromium, or nickel articulations, there were no similar signs of immune reactions. CONCLUSIONS: These histological findings support the possibility of a lymphocyte-dominated immunological response. Although the prevalence of this reaction is low, the persistence or early reappearance of symptoms, including a marked joint effusion and the development of osteolysis, after primary implantation may suggest the possibility of such a reaction.

Several estimators of population differentiation have been proposed in the recent past to deal with various types of genetic markers (i.e., allozymes, nucleotide sequences, restriction fragment length polymorphisms, or microsatellites). We discuss the relationships among these estimators and show how a single analysis of variance framework can accomodate these qualitatively different data types.

We report here a simulation study examining the effect of a recent spatial expansion on the pattern of molecular diversity within a deme. We first simulate a range expansion in a virtual world consisting in a two-dimensional array of demes exchanging a given proportion of migrants (m) with their neighbors. The recorded demographic and migration histories are then used under a coalescent approach to generate the genetic diversity in a sample of genes. We find that the shape of the gene genealogies and the overall pattern of diversity within demes depend not only on the age of the expansion but also on the level of gene flow between neighboring demes, as measured by the product Nm, where N is the size of a deme. For small Nm values (< approximately 20 migrants sent outwards per generation), a substantial proportion of coalescent events occur early in the genealogy, whereas with larger levels of gene flow, most coalescent events occur around the time of the onset of the spatial expansion. Gene genealogies are star shaped, and mismatch distributions are unimodal after a range expansion for large Nm values. In contrast, gene genealogies present a mixture of both very short and very long branch lengths, and mismatch distributions are multimodal for small Nm values. It follows that statistics used in tests of selective neutrality like Tajima's D statistic or Fu's F(S) statistic will show very significant negative values after a spatial expansion only in demes with high Nm values. In the context of human evolution, this difference could explain very simply the fact that analyses of samples of mitochondrial DNA sequences reveal multimodal mismatch distributions in hunter-gatherers and unimodal distributions in post-Neolithic populations. Indeed, the current simulations show that a recent increase in deme size (resulting in a larger Nm value) is sufficient to prevent recent coalescent events and thus lead to unimodal mismatch distributions, even if deme sizes (and therefore Nm values) were previously much smaller. The fact that molecular diversity within deme is so dependent on recent levels of gene flow suggests that it should be possible to estimate Nm values from samples drawn from a single deme.

We formalize the use of allele frequency and geographic information for the construction of gene trees at the intraspecific level and extend the concept of evolutionary parsimony to molecular variance parsimony. The central principle is to consider a particular gene tree as a variable to be optimized in the estimation of a given population statistic. We propose three population statistics that are related to variance components and that are explicit functions of phylogenetic information. The methodology is applied in the context of minimum spanning trees (MSTs) and human mitochondrial DNA restriction data, but could be extended to accommodate other tree-making procedures, as well as other data types. We pursue optimal trees by heuristic optimization over a search space of more than 1.29 billion MSTs. This very large number of equally parsimonious trees underlines the lack of resolution of conventional parsimony procedures. This lack of resolution is highlighted by the observation that equally parsimonious trees yield very different estimates of population genetic diversity and genetic structure, as shown by null distributions of the population statistics, obtained by evaluation of 10,000 random MSTs. We propose a non-parametric test for the similarity between any two trees, based on the distribution of a weighted coevolutionary correlation. The ability to test for tree relatedness leads to the definition of a class of solutions instead of a single solution. Members of the class share virtually all of the critical internal structure of the tree but differ in the placement of singleton branch tips.

Osteoarthritis (OA) is a major disabling disease and is ranked as a major cause of chronic pain in adults. The pathology of the illness is characterized by a loss of articular cartilage leading to narrowing of joint space, increased joint friction, potential structural remodeling, persistent pain, and functional impairment. The proinflammatory cytokine interleukin 1beta (IL-1beta) has several chemical and bioactive characteristics allowing this catabolic protein to be involved in initiation and progression of OA. We review the current understanding of the pathogenesis of OA, and how upregulation of IL-1beta initiates a cascade of intracellular events that can culminate in activation of proteinases, creation of a pro-destructive articular milieu, suppression of anabolic pathways, and a decrease in the synthesis of cartilage extracellular matrix. Therapeutic approaches to block the action of IL-1beta and overcome its signal transduction to curtail disease progression are discussed.

The process by which the Neanderthals were replaced by modern humans between 42,000 and 30,000 before present is still intriguing. Although no Neanderthal mitochondrial DNA (mtDNA) lineage is found to date among several thousands of Europeans and in seven early modern Europeans, interbreeding rates as high as 25% could not be excluded between the two subspecies. In this study, we introduce a realistic model of the range expansion of early modern humans into Europe, and of their competition and potential admixture with local Neanderthals. Under this scenario, which explicitly models the dynamics of Neanderthals' replacement, we estimate that maximum interbreeding rates between the two populations should have been smaller than 0.1%. We indeed show that the absence of Neanderthal mtDNA sequences in Europe is compatible with at most 120 admixture events between the two populations despite a likely cohabitation time of more than 12,000 y. This extremely low number strongly suggests an almost complete sterility between Neanderthal females and modern human males, implying that the two populations were probably distinct biological species.

We sought to quantify the systematic and random errors associated with end-artifacts in the platens compression test for trabecular bone. Our hypothesis was that while errors may depend on anatomic site, they do not depend on apparent density and therefore have substantial random components. Trabecular bone specimens were first tested nondestructively using newly developed accurate protocols and then were tested again using the platens compression test. Percentage differences in modulus between the techniques (bovine proximal tibia [n = 18] and humerus [n = 17] and human lumbar spine, [n = 9]) were in the range of 4-86%. These differences did not depend on anatomic site (p = 0.21) and were only weakly dependent on apparent density and specimen aspect ratio (r2 < 0.10). The mean percentage difference in modulus was 32.6%, representing the systematic component of the end-artifact error. Neglecting the minor variations explained by density and specimen size (approximately 10%), an upper bound on the random error from end-artifacts in this experiment was taken as the SD of the modulus difference (+/-18.2%). Based on a synthesis of data taken from this study and from the literature, we concluded that the systematic underestimation error in the platens compression test can be only approximated and is in the range of 20-40%; the substantial random error (+/-12.5%) confounds correction, particularly when the sample size is small. These errors should be considered when interpreting results from the platens test, and more accurate testing techniques should be used when such errors are not acceptable.

The mitochondrial DNA diversity of 62 human population samples was examined for potential signals of population expansions. Stepwise expansion times were estimated by taking into account heterogeneity of mutation rates among sites. Assuming an mtDNA divergence rate of 33% per million years, most populations show signals of Pleistocene expansions at around 70,000 years (70 KY) ago in Africa and Asia, 55 KY ago in America, and 40 KY ago in Europe and the Middle East, whereas the traces of the oldest expansions are found in East Africa (110 KY ago for the Turkana). The genetic diversity of two groups of populations (most Amerindian populations and present-day hunter-gatherers) cannot be explained by a simple stepwise expansion model. A multivariate analysis of the genetic distances among 61 populations reveals that populations that did not undergo demographic expansions show increased genetic distances from other populations, confirming that the demography of the populations strongly affects observed genetic affinities. The absence of traces of Pleistocene expansions in present-day hunter-gatherers seems best explained by the occurrence of recent bottlenecks in those populations, implying a difference between Pleistocene (approximately 1,800 KY to 10 KY ago) and Holocene (10 KY to present) hunter-gatherers demographies, a difference that occurred after, and probably in response to, the Neolithic expansions of the other populations.

During the past 10 years, there has been a worldwide effort in all medical fields to base clinical health care decisions on available evidence as described by thorough reviews of the literature. Hip fractures pose a significant health care problem worldwide, with an annual incidence of approximately 1.7 million. Globally, the mean age of the population is increasing, and the number of hip fractures is expected to triple in the next 50 years. One-year mortality rates currently range from 14% to 36%, and care for these patients represents a major global economic burden. Surgical options for the management of femoral neck fractures are closely linked to individual patient factors and to the location and degree of fracture displacement. Nonsurgical management of intracapsular hip fractures is limited. Based on a critical, evidence-based review of the current literature, we have found minimal differences between implants used for internal fixation of displaced fractures. Cemented, unipolar hemiarthroplasty remains a good option with reasonable results. In the appropriate patient population, outcomes following total hip arthroplasty are favorable and appear to be superior to those of internal fixation.

The biometrical treatment of laboratory data may require the estimation of a regression line for the transformation of one set of measurements to another. The regression procedure introduced in part I (1) of our work does not always yield unbiased results in such situations, since its estimators are not scale invariant. In part III we present the parameter estimation of a general regression equation which is scale invariant and retains all properties of the method comparison procedure, in particular its robustness. Its application is demonstrated by several examples, and the results are compared with other robust biometrical procedures. The mathematical aspects are explained in the appendix.

We performed extensive and realistic simulations of the colonization process of Europe by Neolithic farmers, as well as their potential admixture and competition with local Palaeolithic hunter-gatherers. We find that minute amounts of gene flow between Palaeolithic and Neolithic populations should lead to a massive Palaeolithic contribution to the current gene pool of Europeans. This large Palaeolithic contribution is not expected under the demic diffusion (DD) model, which postulates that agriculture diffused over Europe by a massive migration of individuals from the Near East. However, genetic evidence in favour of this model mainly consisted in the observation of allele frequency clines over Europe, which are shown here to be equally probable under a pure DD or a pure acculturation model. The examination of the consequence of range expansions on single nucleotide polymorphism (SNP) diversity reveals that an ascertainment bias consisting of selecting SNPs with high frequencies will promote the observation of genetic clines (which are not expected for random SNPs) and will lead to multimodal mismatch distributions. We conclude that the different patterns of molecular diversity observed for Y chromosome and mitochondrial DNA can be at least partly owing to an ascertainment bias when selecting Y chromosome SNPs for studying European populations.

We derive here two new estimators of admixture proportions based on a coalescent approach that explicitly takes into account molecular information as well as gene frequencies. These estimators can be applied to any type of molecular data (such as DNA sequences, restriction fragment length polymorphisms [RFLPs], or microsatellite data) for which the extent of molecular diversity is related to coalescent times. Monte Carlo simulation studies are used to analyze the behavior of our estimators. We show that one of them (mY) appears suitable for estimating admixture from molecular data because of its absence of bias and relatively low variance. We then compare it to two conventional estimators that are based on gene frequencies. mY proves to be less biased than conventional estimators over a wide range of situations and especially for microsatellite data. However, its variance is larger than that of conventional estimators when parental populations are not very differentiated. The variance of mY becomes smaller than that of conventional estimators only if parental populations have been kept separated for about N generations and if the mutation rate is high. Simulations also show that several loci should always be studied to achieve a drastic reduction of variance and that, for microsatellite data, the mean square error of mY rapidly becomes smaller than that of conventional estimators if enough loci are surveyed. We apply our new estimator to the case of admixed wolflike Canid populations tested for microsatellite data.

BACKGROUND: Irrigation and débridement with retention of prosthesis is commonly performed for periprosthetic joint infection. Infection control is reportedly dependent on timing of irrigation and débridement relative to the index procedure. QUESTIONS/PURPOSES: We therefore (1) compared the ability of irrigation and débridement to control acute postoperative, acute delayed, and chronic infections and (2) determined whether any patient-related factors influenced infection control. PATIENTS AND METHODS: We retrospectively reviewed the records of 136 patients (138 joints) from two institutional databases treated with irrigation and débridement between 1996 and 2007. Mean age at time of treatment was 64 years (range, 18-89 years); 77 (56%) joints were in women. Three subgroups were extracted: acute postoperative infections, occurring within 4 weeks (52 joints), acute delayed infections occurring after 4 weeks with acute onset of symptoms (50 joints), and chronic infections (36 joints). Minimum followup was 12 months (average, 54 months; range, 12-115 months). Failure to control infection was reported as the need for any subsequent surgical intervention and/or use of long-term suppressive antibiotics. RESULTS: Infection control was not achieved in 90 joints (65%; 82 requiring return to surgery and eight remaining on long-term suppressive antibiotics). Failure rates were 69% (36 of 52), 56% (28 of 50), and 72% (26 of 36) for acute postoperative, acute delayed, and chronic infections, respectively. Of the 10 variables considered as potential risk factors, only Staphylococcal organisms predicted failure. CONCLUSIONS: Irrigation and débridement is unlikely to control periprosthetic joint infection, including acute infections. Our data suggest surgeons should be cautious using this procedure as a routine means to address periprosthetic joint infection. For most patients, we recommend irrigation and débridement be reserved for an immunologically optimized host infected acutely with a non-Staphylococcal organism. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

The stability and durability of total hip reconstruction is dependent on many factors that include the design and anatomic orientation of prosthetic components. An analysis of femoral component head size and acetabular component orientation shows an interdependency of these variables and joint stability. Increased femoral component head size can increase hip stability by increasing the prosthetic impingement-free range of hip motion and by increasing the inferior head displacement required before hip dislocation. Increasing the femoral head size from 22 mm to 40 mm increases the required displacement for dislocation by about 5 mm with the acetabular component at 45 degrees of abduction; however, increasing acetabular component abduction greatly diminishes this stability advantage of larger femoral heads. Vertical acetabular component orientation and femoral component head subluxation are each predicted to more than double the tensile stress with acetabular component polyethylene compared with components at 45 degrees of abduction. With a desirable acetabular component orientation, the use of larger femoral heads may result in improved joint stability and durable use of polyethylene. With high abduction acetabular component orientation, the use of larger femoral heads contributes little to joint stability and contributes to elevated stress within the polyethylene that may result in implant failure.

Background: Some patients who have a total hip replacement with a second-generation metal-on-metal articulation have persistent or early recurrence of preoperative symptoms. Characteristic histological changes in the periprosthetic tissues suggested the development of an immunological response. Therefore, in order to determine the relevance of these symptoms, we performed a study of the clinical data and periprosthetic tissues associated with endoprostheses with a metal-on metal articulation that had been retrieved at revision. Methods: Periprosthetic tissues as well as the clinical data on the patients were obtained from the first nineteen consecutive revisions performed at the treating hospitals. At the time of the revision, fourteen patients had the metal-on-metal articulation exchanged for either an alumina-ceramic or a metal-on-polyethylene articulation. Five patients received another second-generation metal-on-metal total joint replacement. Five-micrometer sections were prepared from the tissue samples, were stained with routine and immunohistochemical methods, and were examined histologically. Histological specimens from three groups of patients, two of which were treated with non-metal-on-metal implants, served as controls. Results: The majority of patients had persistence of their preoperative pain or early recurrence of the pain after the original total hip replacement, and often a pronounced hip joint effusion had developed after the original replacement. Radiographic follow-up showed the development of radiolucent lines in five hips and of osteolysis in another seven hips. At the revision surgery, both the cup and the stem were found to be well fixed in nine patients. The characteristic histological features were diffuse and perivascular infiltrates of T and B lymphocytes and plasma cells, high endothelial venules, massive fibrin exudation, accumulation of macrophages with droplike inclusions, and infiltrates of eosinophilic granulocytes and necrosis. Only a few metal particles were detected. Immunohistochemical analysis demonstrated that the cellular reaction was still active. The patients who received another second-generation metal-on-metal articulation at the time of the revision had no decrease in symptoms. In the control group of tissues obtained at revisions of endoprostheses without cobalt, chromium, or nickel articulations, there were no similar signs of immune reactions. Conclusions: These histological findings support the possibility of a lymphocyte-dominated immunological response. Although the prevalence of this reaction is low, the persistence or early reappearance of symptoms, including a marked joint effusion and the development of osteolysis, after primary implantation may suggest the possibility of such a reaction.

OBJECTIVE: Each year more than 500 000 children enter out-of-home placement. Few outcome studies of these children specifically address high-risk sexual behavior and adolescent pregnancy. Our study investigated the relationship between living in kinship or foster care and high-risk reproductive behaviors in a nationally representative sample of women. METHODS: Data from 9620 women ages 15 to 44 years in the 1995 National Survey of Family Growth were analyzed in a cross-sectional study. Three groups-foster (n = 89), kinship (n = 513), and comparison (n = 9018)-were identified on the basis of self-reported childhood living situations. Bivariate and multiple linear regression analyses were performed. The outcome variables were age at first sexual intercourse and at first conception and the number of sexual partners. RESULTS: After adjustment for multiple predictor variables, foster care was associated with younger age at first conception (difference: 11.3 months) and having greater than the median number of sexual partners (odds ratio: 1.7, 1.0-2.8). Kinship care was associated with younger age both at first intercourse (difference = 6 months) and at first conception (difference: 8.6 months) and having greater than the median number of sexual partners (odds ratio: 1.4, 1.1-1.8). There were no differences between the kinship and foster groups. CONCLUSIONS: A history of living in either foster or kinship care is a marker for high-risk sexual behaviors, and the risk is comparable in both out-of-home living arrangements. Recognition of these risks may enable health care providers to intervene with high-risk youth to prevent early initiation of sexual intercourse and early pregnancy.

Preserving both cruciate ligaments in unicondylar knee arthroplasty likely provides more normal knee mechanics and contributes to enhanced patient function. It follows that preserving both cruciate ligaments with total knee arthroplasty should provide functional benefit compared to arthroplasty sacrificing one or both cruciates. The purpose of this study was to compare knee kinematics in patients with optimally functioning cruciate-preserving medial unicondylar and bi-unicondylar arthroplasty to determine if knee motions differed. Eight consenting patients with seven medial unicondylar and five bi-unicondylar arthroplasties were studied using lateral fluoroscopy during treadmill gait, stair stepping, and maximum flexion activities. Patient-specific geometric models based on CT and CAD data were used for shape matching to determine the three-dimensional knee kinematics. Tibiofemoral contact locations were computed for the replaced compartments. Maximum flexion in kneeling was 135 degrees +/-14 degrees for unicondylar knees and 123 degrees +/-14 degrees for bi-unicondylar knees (p=0.22). For 0 degrees -30 degrees flexion during the stair activity, the medial condyle translated posterior 3.5+/-2.5 mm in unicondylar knees and 4.7+/-1.9 mm in bi-unicondylar knees (p>0.05). Lateral posterior translation was 5.0+/-2.3 mm in bi-unicondylar knees for 0 degrees -30 degrees flexion. From heel-strike to mid-stance phase, there was little tibial rotation, but unicondylar knees showed 1.5+/-1.6 mm posterior translation of the medial condyle, while bi-unicondylar knees showed 5.1+/-2.2 mm (p<<0.05). The bi-unicondylar knees showed 3.8+/-3.4 mm posterior lateral condylar translation. Preserving both cruciate ligaments in knee arthroplasty appears to maintain some basic features of normal knee kinematics. Knees with bi-unicondylar arthroplasty showed kinematics closer to motions observed in total knee arthroplasty, slightly less weight-bearing flexion, and greater dynamic laxity in gait than unicondylar knees. Despite kinematic differences, knees with unicondylar and bi-unicondylar arthroplasty can provide excellent functional outcomes in appropriately selected patients.

Tissue engineering is an increasingly popular method of addressing pathological disorders of cartilage. Recent studies have demonstrated its clinical efficacy, but there is little information on the structural organisation and biochemical composition of the repair tissue and its relation to the adjacent normal tissue. We therefore analysed by polarised light microscopy and immunohistochemistry biopsies of repair tissue which had been taken 12 months after implantation of autologous chondrocytes in two patients with defects of articular cartilage. Our findings showed zonal heterogeneity throughout the repair tissue. The deeper zone resembled hyaline-like articular cartilage whereas the upper zone was more fibrocartilaginous. The results indicate that within 12 months autologous chondrocyte implantation successfully produces replacement cartilage tissue, a major part of which resembles normal hyaline cartilage.

BACKGROUND: The N-acetyltransferase 2 (NAT2) gene plays a crucial role in the metabolism of many drugs and xenobiotics. As it represents a likely target of population-specific selection pressures, we fully sequenced the NAT2 coding region in 97 Mandenka individuals from Senegal, and compared these sequences to extant data on other African populations. The Mandenka data were further included in a worldwide dataset composed of 41 published population samples (6,727 individuals) from four continental regions that were adequately genotyped for all common NAT2 variants so as to provide further insights into the worldwide haplotype diversity and population structure at NAT2. RESULTS: The sequencing analysis of the NAT2 gene in the Mandenka sample revealed twelve polymorphic sites in the coding exon (two of which are newly identified mutations, C345T and C638T), defining 16 haplotypes. High diversity and no molecular signal of departure from neutrality were observed in this West African sample. On the basis of the worldwide genotyping survey dataset, we found a strong genetic structure differentiating East Asians from both Europeans and sub-Saharan Africans. This pattern could result from region- or population-specific selective pressures acting at this locus, as further suggested in the HapMap data by extremely high values of FST for a few SNPs positions in the NAT2 coding exon (T341C, C481T and A803G) in comparison to the empirical distribution of FST values accross the whole 400-kb region of the NAT gene family. CONCLUSION: Patterns of sequence variation at NAT2 are consistent with selective neutrality in all sub-Saharan African populations investigated, whereas the high level of population differentiation between Europeans and East Asians inferred from SNPs could suggest population-specific selective pressures acting at this locus, probably caused by differences in diet or exposure to other environmental signals.